N n cyanoalkyl n nitroso amino aminoalcohol esters

ABSTRACT

ORGANIC ACID, HALOGENATED ORGANIC ACID AND NITRATE ESTERS OF N-(N-(CYANOALKYL)-N-NITROSO)AMINO-AMINOALCOHOLS, E.G., 4-(N-(1-CYANOETHYL)-N-NITROSO)AMINO-1PIPERAZINE-ETHANOL NITRATE, ARE USEFUL AS ANTI-ANGINAL AGENTS.

"lilnited States Patent O 3,766,185 N-(N-[CYANOALKYL]-N-NITROS)AMINO- AMINOALCOHOL ESTERS William R. J. Simpson, Mendham, N.J., assignor to Sandoz-Wander, Inc., Hanover, NJ.

No Drawing. Continuation-impart of application Ser. No. I

ABSTRACT OF THE DISCLOSURE Organic acid, halogenated organic acid and nitrate esters of N-(N-[cyanoalkyl]-N-nitroso)amino aminoalcohols, e.g., 4- (N-[1-cyanoethyl]-N-nitroso)amino-1- piperazine-ethanol nitrate, are useful as anti-anginal agents.

This application is a continuation-in-part of copending application 131,431 filed Apr. 5, 1971, now abandoned, which is a continuation-in-part of copending applications 51,338 filed June 30, 1970, now abandoned, and 67,994 filed Aug. 28, 1970, now abandoned.

This invention relates to organic acid, halogenated organic acid and nitrate esters of N-nitrosoamino-acetonitrile derivatives. More particularly, this invention concerns organic acid, halogenated organic acid and nitrate esters of N-(N-[cyanoalkyl]-N-nitroso)amino-aliphatic and cyclic aminoalcohols, their preparation and their use in pharmaceutical compositions.

The compounds of this invention may be represented by the following structural formula where R and R each independently represents hydrogen or lower alkyl, i.e., alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, isopropyl and the like;

R represents -(R )CH X.; and

X represents R and R each independently represents straight or branched chained alkylene having 1 to 7 carbon atoms, e.g., methylene, ethylene, t-butylene, and the like; and

R represents lower alkyl as defined above or lower alkyl as defined above substituted with l to 3 halo atoms having an atomic weight of from about 19 to 36 e.g., trifluoromethyl, trichloromethyl, c pdichloroethyl and the like; or 1 R and R, together with N represent where p is 4, 5 or 6;

q is 0 or 1;

X is as defined above; and

R is lower alkylene, i.e., alkylene having 1 to 3 carbon atoms, e.g., methylene, ethylene, isopropylene and the like;

provided that --(R X is not attached to a carbon atom adjacent to the nitrogen atom when q is 0.

The process for preparing the compounds of Formula I may be represented by the following reaction scheme:

R4 No R] Rs N0 R1 Esteriiication l /N-NC-CN N-N-(f-CN R4 2 R4 R:

(H) (I) where R R R and R are as defined above;

R, and R are as defined above; or R and R together with N represent where p, q and R are as defined above; and

provided that (R -OH is not attached to a carbon atom adjacent to the nitrogen atom when q=0.

The compounds of the Formula I are prepared by esterifying the compounds of Formula II with a nitrating or acylating agent. The esterification is carried out under non-acidic or weakly acidic conditions to prevent cyclization of the compounds (I) or (II) where R or R is hydrogen.

The nitration is carried out with conventional nitrating agents, preferably a mixture of nitric acid or metal nitrate and a carboxylic acid anhydride having 3 to 8 carbon atoms, especially acetic anhydride. It is preferred that the nitration be carried out at temperatures between about minus C. to 50 C., especially at about 15 C. to 20 C. The reaction is also preferably carried out in excess reagent, especially excess carbovylic acid anhydride or a mixture of carboxylic acid anhydride and organic acid. If desired, inert organic solvents, in particular tetrahydrofuran, may be used. The nitrating agent, the temperature and the particular solvent used are not critical.

The acylation is carried out using conventional acylating agents of the formula.

0 Rr-ll-Y (III) where Y represents halo having an atomic weight of from about 35 to or O -O l-R1 where R; is as defined above and each R, of the compound of the formla is the same. With non-halogenated organic acid anhydride acylating agents, no special precautions are necessary to maintain the reaction conditions non-acidic. However, when halogenated acid anhydride acylating agents or halogenated or unsubstituted acid halide acylating agents are used, a binding agent, e.g., pyridine, is used to maintain the requiredynon-acidic conditions." The'te'mperature at which the acylation iscarried out is not critical, but it is preferred that it be run at temperatures between about l C. to about +30 C. Although a solvent is not required, it is preferred that the reaction be carried out in the presence of an inert non-acidic solvent, especially the halogenated lower alkanes such as methylene dichloride and the like. If desired, excess non-halogenated acid anhydride can be employed as solvent when it is the acylating agent in the process.

The compounds of Formula I are recovered by conventional techniques, e.g., evaporation. The compounds (I) in which R and R together with N form a piperazine ring may also be recovered in the form of their pharmaceutically acceptable weak organic acid addition salts where R represents --(R )-CH,-Z; R represents -(R )-CH or, -(R,)-CH --Z; or

R, and R together with N represent -N /N(R|)Z 0r 2)n N- where Z represents OH or i 0 2-111; and

1, a, 3, R R R R R,;, p, q and the pror viso are as set out previously.

The nitration of the compounds of Formula IV is carried out in the same manner as described above for the nitration of the compounds of Formula II. It will be appreciated that where either R or R or both are an organic acid ester, the R and R of the product will also be an organic acid ester. That is to say the nitration step nitrates R and R only when they contain a hydroxy group.

The compounds of Formulae II and IV, in which both R and R are lower alkyl are novel and represent another aspect of this invention. Compounds II) in which R and R are alkyl and compounds (IV) in which Z is 01-1 are prepared in accordance with the following reacwhere R andk 'ea'ch independently represen't'lower alkyl, as

defined above; and R R and the proviso are as set out previously The compounds of Formula IV are prepared by treating in acidic aqueous solvent the compounds of Formula V with the ketones of Formula VI in the presence of cyanide-anion, The acid used to acidify the solvent can be any of the water soluble inorganic or organic acids, espe cially hydrochloric acid, sulfuric acid, and acetic acid. The cyanide anion is prepared in situ in the usual manner by reaction of an alkali metal cyanide with the acidic medium of the reaction. The preferred solvent is water; but mixtures of water and water miscible solvent, such as excess ketone (VI) or the lower alkanols, may be used if desired. Although the temperature of the reaction is not critical, it is conveniently carried out at temperatures of between --15 to +20 0., preferably between -10 to +15 C. The product (IV) is recovered by conventional techniques, e.g., extraction and evaporation.

The compounds of Formula II' are prepared by treating the compounds ofFormula IV with nitrous acid under the same condition as used in the preparation of the compound of Formula IV. The nitrous acid is prepared in situ by the reaction of an alkali metalnitrite with the acid medium of the reaction.- Although the solvent and temperature are not critical, the preferred conditions are the same as in the preparation of the compound of Formula IV. The product (11') is recovered by conventional techniques e.g., extraction and evaporation.

The compounds of Formula IV in which Z is may be prepared according to the following reaction scheme:

R represents -R )--CH or (R0) Hr-O (IE1 or I R and R together with N represent (Ru -0&1

V -N N-(ntpo n r 11,), N-

and 1 2' a', 4, 5, R6, R R p, q, and the proviso are as set out previously, 7

known and may be prepared according to methods disclosed in the literature from known materials. The compounds of Formulae III and V and II and IV wherein one or both of R and R are hydrogen which are not specifically disclosed in the art may be prepared by analogous methods from known materials.

As indicated previously, the compounds of Formula I are useful because they possess pharmacological activity in animals. In particular, the compounds are useful as anti-anginal agents as indicated by an increase in coronary blood flow and by a reduction of myocardial oxygen consumption in an anesthetized dog given 0.5 to milligrams per kilogram of body weight of a compound of Formula I intravenously.

For such usage, compound ('I) may be administered orally or parenterally, preferably sublingually, as such or admixed with conventional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs, and parenterally as solutions, suspensions, dispersions, emulsions, and the like, e.g., a sterile injectable aqueous suspension. The composition for oral use may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutically accpetable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., starch, gelatin acacia, and lubricating agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions, e.g., suspending agents (methylcellulose, tragacanth and sodium alginate), wetting agents (lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monoleate) and preservatives (ethyl-p-hydroxy benzoate). Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated as known in the art and may contain appropriate dispersing or wetting agents and suspending agents identical or similar to those mentioned above. These pharmaceutical preparations may contain up to about 90% of the active ingredient in combination with the carrier or adjuvant.

The anti-anginal effective dose of active ingredient employed for the treatment of angina may vary depending on the particular compound employed and the severity of the condition being treated. However, in general, satisfactory results are obtained when the compounds (I) are administered at a daily dosage of from about 0.01 milligram to about 25 milligrams per kilogram of animal body weight, preferably given in divided doses two to four times a day, or in sustained release form. For most large mammals, such as primates, in need of said treatment, the total daily dosage is from about 0.7 to about 50 milligrams. Dosage forms suitable for internal use comprise from about 0.175 to about 25 milligrams of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.

The preferred pharmaceutical compositions from the standpoint of preparation and case of administration are The following pharmaceutical compositions are formulated with the indicated amount of active agent using conventional techniques. The injectable suspension and the oral liquid suspension represent formulations useful as unit doses and may be administered in the treatment of angina pectoris. The injectable suspension is suitable for administration once a day where as the oral liquid suspension is suitable administered 2 to 4 times per day for this purpose:

Liquid suspension 4-(N-[l-eyanoethyH-N-nitroso) amino'lpiperazine ethanol nitrate maelate Sodium carboxy methylcelluslose, U.S Methyl cellulose Polyvinylpryrolidone. Lecithin Methyl paraben, U.S.P Propyl paraben, U.S.P Polysorbate (e.g. Tween 80), U. Sorbitol solution 70%, U.S.P ginger agent to adjust pH for desired stability a er l For injection, q.s. to 1 ml. 2 q.s. to 5 ml.

EXAMPLE 1 4-(N-[ l-cyanoethyl] -N-nitroso amino-l-piperazineethanol-nitrate A solution of 6.42 g. of 4-(N-[ l-cyanoethyl]-N-nitroso) amino-l-piperazine ethanol in 2 ml. of tetrahydrofuran is added over a period of 6 minutes dropwise to a stirred cooled (-10 to -5 C.) mixture of 11.9 ml. of acetic anhydride and 3.95 ml. of nitric acid.

The resulting mixture is poured into ice water containing excess ammonia mixture. The crystalline product obtained is filtered off, washed with water and dried under vacuum. The solid is then triturated with ether after which the combined extracts are filtered and partially evaporated. Heptane is added to precipitate the final product, 4-(N [1-cyanoethyl]-N-nitroso)amino-l-piperazine-ethanol-nitrate (M.P. 5 8-60 C.).

When the above 4-(N-[l-cyanoethyl1-N-nitroso) aminol-piperazine ethanol nitrate is treated with maleic acid in ether there is obtained 4-(N-[l-cyanoethyl]-N-nitroso) amino-l-piperazine ethanol nitrate maleate (M.P. to 106 C.).

When 1- (N- l-cyanoethyl] -N-nitroso amino-4-piperidinol, 1- (N-[ l-cyanoethyl] -N-nitr0s0 amino-4-piperidin ethanol, N- N- 1-cyanoethyl1-N-nitroso) amino-imidodiethanol or 2-(N [N-cyanomethyl-N-nitroso]amino-N- ethylamino)ethanol is used in place of 4-(N-[l-cyanoethyl]-N-nitroso)amino-l-piperazine-ethanol in the above reaction, there is obtained the maleate salt of l-(N-[lcyanoethyH-N-nitroso)amino-4-piperidinol nitrate; l-(N- l-cyanoethyl] -N-nitroso amino-4-piperidin ethanol nitrate; N-(N-[1 cyanoethyl]-N-nitroso)amino-imidodiethanol dinitrate; or 2-(N- [N-cyanomethyl-N-nitroso] amino-N-ethylamino)ethanol nitrate, respectively.

EXAMPLE 2 4-(N-[Z-cyanoisopropyl]-N-nitroso)amino-1 piperazine ethanol-nitrate (a) 4- (N- [2-cyanoisopropyl] -N-nitroso amino-l-piperazine ethanol-To a solution of 5.8 g. of 4-amino-1- piperazine-ethanol in 15 ml. of water acidified withv 3.8 ml. of concentrated hydrochloric acid at a temperature of C. is added 2.66 g. of potassium cyanide in ml. of water. The mixture is stirred for 5 minutes 'and- 2.5 gms. of acetone are added after which the reactants are stored overnight in a refrigerator. After standing overnight, 6.6 ml. of concentrated hydrochloric acid is added to this solution at about 10 C. followed dropwise by 3.5 g. of sodium nitrite dissolved in ml. of water. After addition is complete, the reaction mixture is cooled to about 0 C. and neutralized with concentrated ammonium hydroxide. The product, 4-(N-[2-cyanoisopropyl N-nitroso) amino-l-piperazine ethanol, is extracted with chloroform and recovered by evaporation.

(b) 4 (N [2 cyanoisopropyl] N nitroso)aminol-piperazine ethanol nitrate.When the 4-(N-[2-cyanoisopropyl]-N-nitroso)amino-l-piperazine ethanol above is treated in accordance with the process of Example I, in place of 4-(N-[l-cyanoethyl]-N-nitroso)amino-l-piperazine ethanol, there is obtained 4-(N-[2-cyanoisopropyl]- N-nitroso)amino-l-piperazine ethanol nitrate. This product is treated with maleic acid in ether to yield 4-(N-[2- cyanoisopropyl]-N-nitroso)amino l piperazine ethanol nitrate maleate (M.P. 124 C.).

EXAMPLE 3 4- (N- Z-cyanoisopropyl] -N-nitroso amino-lpiperazine ethanol-nitrate To a solution of 5.8 g. of 4-amino-1-piperazine-ethanol in 15 ml. of water acidified with 3.8 ml. of concentrated hydrochloric acid at a temperature of 5 C. is added 2.66 g. of potassium cyanide in 10 ml. of water. The mixture is stirred for 5 minutes and 2.5 gms. of acetone are added after which the reactants are stored overnight in a refrigerator.

After evaporating off the solvent, the 4-(N-[2-cyanoisopropyl])amino-l-piperazine ethanol is dissolved in 2 ml. of acetic acid and added over a period of 6 minutes dropwise to a stirred cooled (-l0 to -5 C.) mixture of 18 ml. of acetic anhydride and 6.00 ml. of 90% nitric acid.

The resulting mixture is poured into ice water containing an excess of ammonia solution. The crystalline product obtained is filtered off, washed with water and dried under vacuum. The solid is then triturated with ether after which the combined extracts are filtered and partially evaporated. Heptane is added to precipitate the final product, 4 (N-[2-cyanoisopropyl]-N-nitroso)amino-1- piperazine-ethanol nitrate (M.P. 58-60 C.). The product is treated with maleic acid in ether to yield 4-(N-[2- [2-cyanoisopropyl]-N-nitroso)amino-l-piperazine ethanol nitrate maleate.

When the above process is carried out using an equivalent amount of formaldehyde in place of the acetone, there is obtained 4-(N-cyanomethyl-N-nitroso)amino-lpiperazine ethanol nitrate.

EXAMPLE 4 4- (N- l-cyanoethyl] -N-nitroso) aminol-piperazine ethanol acetate To a solution of 1.0 g. of 4-(N-[l-cyanoethyl]-N- nitroso)amino-l-piperazine ethanol in 10 ml. of methylene dichloride is added 0.5 g. of acetic anhydride at 5 C.

The resulting mixture is added to 30 ml. of methylene dichloride and the solution formed is washed With 10% sodium carbonate solution. The organic phase is dried; and evaporation yields the final product, 4-(N-[l-cyanoethyl]-N-nitroso)amino-l-piperazine ethanol acetate as a pale yellow oil. When the product is treated with maleic acid in ether, there is obtained 4-(N-[1-cyanoethyl1-N- nitroso)amino-l-piperazine ethanol acetate maleate.

When 1- N- l-cyanoethyl] -N-nitros0 amino-4-piperidinol, l-(N-[l-cyanoethyl] N nitroso)amino-4-piperazine ethanol, N-(N-[l cyanoethyl1-N-nitroso)aminoimido diethanol or 2-(N-[N-cyanomethyl-N-nitroso]amino-N-butyl amino)ethanol is used in place of 4-.(N-[1- cyanoethyl]N-nitroso)amino-l-piperazine ethanol in the above reaction, there is obtained 1-(N-[1- cyanoethyl]-N- nitroso)amino-4-piperidinol acetate; 1-(N-[l-cyanoethyl1- N-nitroso)amino-4-piperidine ethanol acetate, N-(N-[lcyanoethyl]-N-nitroso)amino-imido diethanol diacetate; or 2- N-[N-cyanomethyl-N-nitroso]amino-N-butyl amino)ethanol acetate, respectively.

Following the procedure of this example for preparing 4-( N- l-cyanoethyl] -N-nitroso) amino-l-piperazine ethanol acetate but using an equivalent amount of trifiuoro acetic anhydride in place of the acetic anhydride used therein and adding an excess of pyridine to bind the acid liberated in the reaction, there is obtained 4-(N-[l-cyanoethylJ-N-nitroso)amino-l-piperazine ethanol trifiuoro ace: tate.

EXAMPLE 5 4- (N- 2-cyanoisopropyl] -N-nitr0s0 aminol-piperazine ethanol-acetate '(a) 4-(N-[2-cyanoisopropyl]-N-nitroso)amino-l-piperazine ethanol.-To a solution of 5.8 g. of 4-amino-l-piperazine-ethanol in 15 ml. of water acidified with 3.8 m1. of concentrated hydrochloric acid at a temperature of 5 C. is added 2.66 g. of potassium cyanide in 10 ml. of water. The mixture is stirred for 5 minutes and 2.5 gms. of acetone are added after which the reactants are stored overnight in a refrigerator. After standing overnight, 6.6 ml. of concentrated hydrochloric acid is added to this solution at about 10 C. followed dropwise by 3.5 g. of sodium nitrite dissolved in 15 ml. of water. After addition is complete, the reaction mixture is cooled to about 0 C. and neutralized with concentrated ammonium hydroxide. The product, 4(N-[2-cyanoisopropyl]-N-nitroso)amino-l piperazine ethanol, is extracted with chloroform and recovered by evaporation.

(b) 4- (N- [Z-cyanoisopropyl] -N-nitroso amino-l-piperazine ethanol acetate-When the 4-(N-[2-cyanoisopropyIJ-N-nitroso)amino-l-piperazine ethanol is treated with acetic anhydride in accordance with the process of Example 4, in place of 4-(N-[l-cyanoethyl]-N-nitroso)amino l-piperazine ethanol, there is obtained 4-(N-[2-cyanoisopropyl]-N-nitroso)amino 1 piperazine ethanol acetate. This product is treated with maleic acid in ether to yield 4 (N-[Z-cyanoisopropyl]-N-nitroso)amino-l-piperazine ethanol acetate maleate (M.P. 134-136 C.).

EXAMPLE 6 4- (N-[2-cyanoisopropyl]-N-nitroso)-1-piperazine ethanol acetate When the 4 (N-[Z-cyanoisopropyl])amino-l-piperazine ethanol of Example 3 is treated with acetic anhydride in accordance with the process of Example 4, there is obtained 4-(N-[2-cyanoisopropyl])amino-l-piperazine ethanol acetate which when treated with additional acetic anhydride and nitric acid in accordance with the process of Example 1, yields 4 (N-(N-[2-cyanoisopropyl] N- nitro)amino-l-piperazine-ethanol acetate.

What is claimed is:

1. A compound of the formula No R where R and R each independently represents hydrogen or lower alkyl having 1 to 4 carbon atoms; X represents R represents lower alkyl having 1 to 4 carbon atoms or lower alkyl having 1 to 4 carbon atoms substituted with 1 to 3 halo atoms having an atomic weight between about 19 to 36; and R is lower alkylene having 1 to 3 carbon atoms. 2. The compound of claim 1 which is 4-(N-[2-cyanoisopropyl]-N-nitroso)amino-l-piperazine ethanol acetate. 3. The compounds of claim 1 in the form of their maleate salts.

4. A compound of the formula No R;

aim-ON 5. The compound of claim 1 which is 4-(N-[1-cyanoethylJ-N-nitroso)amino-l-piperazine-ethanol nitrate.

10 6. The compound of claim 1 which is 4-(N-[2-cyanoisopropyl]-N-nitroso)amino-l-piperazine ethanol nitrate.

References Cited UNITED STATES PATENTS 3,312,690 4/1967 Masuda 260-268 N 3,470,182 9/1969 Hardtmann 260-268 N 3,637,700 1/1972 Gabel et a1. 260-256.5 R 3,637,700 1/ 1972 Fabel et al 260-256.S R 3,637,701 1/7972 Gabel et al. 260-256.4 Q 3,642,793 2/1972 Imashiro 260-268 N DONALD G. DAUS, Primary Examiner US. Cl. X.R. 260-294.9, 999 

